Autophagy as a lysosomal degradation pathway plays an essential role in cell survival, differentiation, development and homeostasis. This cellular degradation pathway has been reported to be implicated in the development of vascular diseases such as atherosclerosis and restenosis through its deleterious actions during inappropriate activation. However, little is known how the pro-survival function of autophagy contributes to vascular regulation under physiological condition and what occurs if there is defect or deficiency of autophagy in vascular cells. The present proposal will test a central hypothesis that a CD38-ADP-ribosyslcyclase signaling pathway controls the autophagic process in coronary arterial smooth muscle cells (CASMCs) via its lysosomal regulation and thereby protects these cells from atherosclerotic injury preventing atherosclerosis. Defect of this lysosome regulation in autophagy may induce or accelerate coronary atherosclerosis during hyperlipidemia or hypercholesteremia. To test this hypothesis, three Specific Aims are proposed. Specific Aim 1 will determine whether regulated lysosomes via CD38-ADP-ribosylcyclase signaling pathway contribute to autophagy upon proatherosclerotic stimuli and to explore related molecular mechanisms using CASMCs from CD38-/- and CD38+/+ mice. Specific Aim 2 attempts to test whether the abnormality of lysosome regulation results in impaired autophagy of CASMCs and atherosclerosis in vivo in CD38-/- mice with or without rescuing CD38-APD-ribosylcyclase gene and in CD38+/+ mice with locally silenced CD38-APD-ribosylcyclase gene. In Specific Aim 3, we will examine how the deficiency of autophagy associated with deranged lysosomes induces dysfunction of CASMCs and atherosclerosis and then define the mechanisms mediating the actions of accumulated autophagosomes in cells and coronary arterial wall. To our knowledge, these proposed studies will provide the first experimental evidence that the deficiency of autophagy in CASMCs due to dysregulation of lysosome function via CD38-ADP-ribosyslcyclase signaling pathway is an important molecular mechanism leading to coronary atherosclerosis. The findings may suggest new therapeutic strategy for treatment or prevention of atherosclerosis by improvement of lysosomal function or regulation in coronary arteries. PUBLIC HEALTH RELEVANCE: Autophagy is a cell function, meaning 'to eat oneself', which is responsible for the degradation and recycle of used and damaged proteins and other components within cells, ensuring cell survival. This grant proposal seeks to examine how this cell self- protective function is fine controlled in arteries of the heart and to investigate whether and how the loss of such fine control of autophagy causes arterial diseases such as coronary heart disease. We will demonstrate that a membrane signaling protein, CD38 plays a central role in the control of autophagy and its defect may result in coronary arterial disease and consequent heart attack. Our findings will for the first time link the deficient autophagy in heart vessels to heart disease and may help develop new therapy in the future for more effective treatment of coronary arterial disease and prevention of heart attack.